LW-214, a newly synthesized flavonoid, induces intrinsic apoptosis pathway by down-regulating Trx-1 in MCF-7 human breast cells
LW-214, a newly synthesized flavonoid, induces intrinsic apoptosis pathway by down-regulating Trx-1 in MCF-7 human breast cells
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LW-214 是一种新合成的类黄酮，通过下调 MCF-7 人乳腺细胞中的 Trx-1 诱导内在凋亡途径。
DOI：
10.1016/j.bcp.2013.12.010
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发表时间：
2014-02-15
影响因子：
5.8
通讯作者：
Guo, Qinglong
中科院分区：
文献类型：
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作者：
Pan, Di;Li, Wei;Guo, Qinglong
本研究探讨了新合成的黄酮类化合物LW-214对MCF-7人乳腺癌细胞的抗肿瘤作用及其机制。LW-214通过增加Bax/Bcl-2比率、线粒体膜电位（Δ Psi（m））和半胱天冬酶-9活化的损失、聚（ADP-核糖）聚合酶（PARP）降解、细胞色素c（Cyt c）释放和凋亡诱导因子（AIF）转座来触发线粒体凋亡途径。进一步的研究表明，LW-214通过下调硫氧还蛋白-1（Trx-1）的表达诱导活性氧（ROS）的产生和凋亡信号调节激酶1（ASK 1）的激活。ROS升高和ASK 1激活可诱导c-Jun N-末端激酶（JNK）持续磷酸化，而JNK抑制剂SP 600125几乎可逆转LW-214诱导的MCF-7细胞凋亡。Trx-1在MCF-7细胞中的过表达减弱了LW-214介导的细胞凋亡以及JNK激活，并逆转了线粒体凋亡相关蛋白的表达。因此，体内研究表明，LW-214在接种MCF-7肿瘤的BALB/c小鼠中表现出潜在的抗肿瘤作用，全身毒性较低，其机制与体外研究相同。这些结果表明，LW-214可能通过下调Trx-1的功能，导致细胞内ROS的产生和ASK 1的释放，进而激活JNK，从而诱导线粒体凋亡。(C)2013 Elsevier Inc. All rights reserved.
In this study, the anticancer effect of LW-214, a newly synthesized flavonoid, against MCF-7 human breast cancer cells and the underlying mechanisms were investigated. LW-214 triggered the mitochondrial apoptotic pathway by increasing Bax/Bcl-2 ratio, loss of mitochondria] membrane potential (Delta Psi(m)) and caspase-9 activation, degradation of poly (ADP-ribose) polymerase (PARP), cytochrome c (Cyt c) release and apoptosis-inducing factor (AIF) transposition. Further research revealed that both the reactive oxygen species (ROS) generation and the apoptosis signal regulating kinase 1 (ASK1) activation by LW-214 were induced by down-regulating the thioredoxin-1 (Trx-1) expression. The ROS elevation and ASK1 activation induced a sustained phosphorylation of c-Jun N-terminal kinase (JNK), while SP600125, as known as JNK inhibitor, almost reversed LW-214-induced apoptosis in MCF-7 cells. Overexpression of Trx-1 in MCF-7 cells attenuated LW-214-mediated apoptosis as well as the JNK activation and reversed the expression of mitochondria] apoptosis-related protein. Accordingly, the in vivo study showed that LW-214 exhibited a potential antitumor effect in BALB/c species mice inoculated MCF-7 tumor with low systemic toxicity, and the mechanism was the same as in vitro study. Taken together, these findings indicated that LW-214 may down-regulated Trx-1 function, causing intracellular ROS generation and releasing the ASK1, and lead to JNK activation, which consequently induced the mitochondrial apoptosis in vitro and in vivo. (C) 2013 Elsevier Inc. All rights reserved.